We have previously identified in Drosophila loss-of-function mutations in spinster ( spin), an endosomal protein, that give rise to shortened lifespan, accumulation of lipofuscin, swollen lysosomes, neurodegeneration, and synaptic overgrowth ( 9– 12), all hallmarks of LSD. The pathways by which OS/ROS go on to contribute to neuronal dysfunction in aging or diseased tissue currently remain obscure ( 8). 7) and may in turn induce a further increase in autophagy. Oxidative stress (OS), potentially activated by lysosomal accumulation, is an increasingly recognized feature of LSDs (see for example ref. A similar mechanism may occur in LSD, where lysosomal dysfunction can lead to an accumulation of autophagosomes, either because of a defect in autophagosomal clearance in the lysosome or an induction of autophagy ( 5, 6). Lipofuscin deposition is proposed to hamper autophagic degradation in general and particularly organelle turnover, promoting the accumulation of senescent mitochondria and lysosomal iron, producing increasing amounts of reactive oxygen species (ROS) ( 4).
Ectopic synaptogenesis and dendritogenesis has also been demonstrated in models of LSDs ( 2, 3), although the mechanisms causing this growth are unclear. Lysosomal storage disorders (LSD) are characterized in part by lipofuscin accumulation, reduced lysosomal function, and neurodegeneration.
Lipofuscin is viewed as a hallmark of aging cells and is notable in long-lived cells, such as neurons. During aging, this “waste” manifests as lipofuscin, a nondegradable, autofluorescent intralysosomal polymeric agglomeration of lipids and proteins ( 1). Lysosomal dysfunction leads to poor digestion of damaged macromolecules and organelles, resulting in the accumulation of biological waste. Our data describe a previously unexplored link between oxidative stress and synapse overgrowth via the JNK signaling pathway. In support of this suggestion, we report here that impaired autophagy function reverses synaptic overgrowth in spin. In LSD, increased autophagy contributes to lysosomal storage and, presumably, elevated levels of oxidative stress. These data suggest that ROS, via activation of the JNK signaling pathway, are a major regulator of synapse overgrowth. Similarly, inhibiting JNK, fos, and jun activity in animals with excessive oxidative stress rescues the overgrowth phenotype. Inhibiting JNK and fos activity in spin rescues synapse overgrowth and electrophysiological deficits. Furthermore, JNK and fos in turn are known potent activators of synapse growth and function. ROS are known to stimulate JNK and fos signaling. Synapse overgrowth was also observed in mutants defective for protection from ROS and animals subjected to excessive ROS. Reducing ROS in spin mutants rescues synaptic overgrowth and electrophysiological deficits. Here we identify a reactive oxygen species (ROS) burden in spin that may be attributable to previously identified lipofuscin deposition and lysosomal dysfunction, a cellular hallmark of LSD. In previous work, we identified a Drosophila model of lysosomal storage disease (LSD), spinster ( spin), with larval neuromuscular synapse overgrowth. The physiological constraints and demands that regulate appropriate synaptic growth and connectivity are currently poorly understood. Synaptic terminals are known to expand and contract throughout an animal's life.
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